Hoping to uncover critical mechanisms needed to develop effective chemotherapeutic approaches for an aggressive form of lung cancer, Priyamvada Rai, Ph.D., assistant professor of medicine in the Division of Gerontology and Geriatric Medicine, will study a novel gene associated with non-small cell lung carcinoma with a $1.5 million, five-year grant she received from the NIH’s National Cancer Institute.

For the grant, “MutT Homolog 1 (MTH1) as a Novel Mediator of RAS Oncogene-Induced Pro-Malignant Pathways,” Rai will study the protein MTH1, which eliminates oxidized DNA precursors and is elevated in patients with non-small cell lung carcinoma (NSCLC). Rai hopes to use MTH1 as a prognostic marker and therapeutic target to improve treatment for tumors that carry mutations in the RAS oncogene, the most common oncogene in human cancer.

“Many NSCLC tumors carry the RAS oncogene, which makes them extremely aggressive and treatment-resistant and which has proven difficult to target directly,” said Rai, who is a member of the Sylvester Comprehensive Cancer Center. “Our study focuses on investigating MTH1 as a key facilitator of multiple RAS-associated malignant pathways that allow tumors to grow and survive chemotherapy.”

Rai, who joined the Miller School in 2008, and her team are working to identify the protective cellular mechanisms co-opted by RAS-transformed tumors that allow the tumors to evade oncogene-generated stresses and the resulting tumor growth suppression. Understanding these mechanisms, Rai says, is critical for developing effective clinical applications to combat oncogenic RAS-driven cancers.

“We believe that oxidative stress produced by the RAS oncogene causes NSCLC cells to become ‘addicted’ to MTH1,” said Rai. “So we anticipate that shutting down MTH1 will be a highly effective therapeutic option for these tumors, with few systemic side effects.”

Co-investigators on the grant, which began June 1, include Dao Nguyen, M.D., professor of surgery and Chief of the Thoracic Surgery Section in the Division of Cardiothoracic Surgery, and Anthony Capobianco, Ph.D., professor of surgery and Director of the Molecular Oncology Program in the Division of Surgical Oncology.